Therapeutic Efficacy of Chinese Patent Medicine Containing Pyrite for Fractures: A Systematic Review and Meta-Analysis

Background and Objectives: Korean and traditional Chinese medicine state that pyrite is effective for fracture treatment, but supporting clinical data are limited. This systematic review aimed to investigate the therapeutic role of Chinese patent medicine containing pyrite (CPMP) in clinical treatment for fractures. Materials and Methods: Seven electronic databases were searched using the keywords “pyrite”, “pyritum”, and “zirantong” between inception and December 2022, yielding 29 published clinical studies. Randomized controlled trials that included CPMP were considered eligible regardless of the fracture type. Quality assessment and meta-analysis of the included RCTs were also performed. Results: Most studies showed high heterogeneity (I2 > 50%) and significant results (p < 0.05). Compared to the results of the control group, CPMP was more effective in terms of the primary outcome related to the efficacy rate, including the total effective rate, callus growth rate, bone union, and edema disappearance time (all p < 0.00001) and in terms of secondary outcomes related to pain reduction, namely pain intensity and pain disappearance time, than the control group (both p < 0.01). CPMP was more effective than the control group in terms of erythrocyte sedimentation rate (p < 0.01), hematocrit (p < 0.01), erythrocyte aggregation (p < 0.05), and plasma viscosity (p < 0.05). CPMP did not cause serious side effects, and the incidence of complications was significantly less than that in the control group. Conclusions: CPMP may be a safe and effective alternative treatment for fractures and may be beneficial in preventing postoperative complications, reducing pain, relieving symptoms, and accelerating healing.


Introduction
Bone is a complex mineralized connective tissue arranged in a multi-scale hierarchical configuration, and there is a strong dependence between the mechanical properties of bone and its meso-and microstructural arrangement [1].This complexity of bone is also being exploited for torsion-resistant bio-inspired solutions in the medical field [2].Bone has stress-concentrating features such as natural voids and defects, as well as voids caused by pathological conditions or created during surgery.These features reduce the mechanical integrity of the bone, making it more susceptible to sudden brittle fracture during trauma or gradual fatigue failure over time.Large defects caused by disease and surgery can create holes, notches, sharp edges, and cracks [3].In severe fractures, hemorrhagic shock due to blood vessel damage can be life threatening, and in some cases, may damage the internal organs [4,5].In 2019, 178 million new fractures were reported worldwide, representing a 33.4% increase since 1990 [6].Fractures are a global public health challenge that can lead to a high burden on individuals, families, societies, and healthcare systems through reduced productivity, disability, reduced quality of life, and high healthcare costs [7][8][9].
A common fracture treatment approach is fixing the broken bone with a cast and administering anti-inflammatory drugs to relieve pain and inflammation [10].However, anti-inflammatory drugs greatly decrease fracture treatment efficiency by inhibiting COX-1 and COX-2 functions, which play important roles in the early recovery from fractures [11]; thus, their use has been avoided.It is recommended to take an overdose of calcium in addition to vitamin D, which acts as a calcium absorption supplement, although the overdose can cause various side effects such as vomiting, diarrhea, and convulsions [12].The most commonly used drugs include bisphosphonates, teriparatide, and parathyroid hormone; however they can cause serious side effects, such as jawbone necrosis, dyspnea, tissue damage, gastroesophageal reflux disease, rash, joint pain, and headache [13].Movement restriction due to the long duration associated with t fracture treatment can cause pneumonia, deep vein thrombosis, reduced maintenance of physical function, and quality of life [14,15].Therefore, it is crucial to develop an economical fracture treatment agent that promotes bone formation, has few side effects, and is easy to administer [16,17].
Recently, market interest has shifted from developing single and complex compounds with various side effects to novel natural drugs and product extracts with relatively low side effects and multiple mechanisms of action [18,19].The Republic of Korea, China, and Japan have a long history of the clinical use of natural products with well-established systematic records and traditional theories [19].Pyrite has been used in traditional mineral medicine in the Republic of Korea and China for thousands of years.It eliminates blood stasis and connects muscles and bones [20] and has been widely used in fracture treatment [21].In Korean medicine (KM), pyrite is often used alone or as a component of combination treatment in clinical practice; however, there have been few clinical studies examining its effect [22].In traditional Chinese medicine (TCM), several clinical studies using pyrite have been reported.Particularly, Chinese patent medicine (CPM) containing pyrite (CPMP) has been used for fracture treatment [23,24] although a comparative analysis of CPMP efficacy in fracture treatment is lacking.Therefore, this study systematically reviewed the currently available literature and performed a meta-analysis regarding CPMP efficacy and safety in clinical practice.

Materials and Methods
The protocol for this systematic review was previously published [25] and registered in the International Prospective Register of Systematic Reviews (PROSPERO).This systematic review was reported in compliance with the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) [26].

Data Sources and Search Strategy
Seven electronic databases, namely EMBASE, PubMed, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), Korean Studies Information Service System (KISS), National Digital Science Library (NDSL), and Oriental Medicine Advanced Searching Integrated System (OASIS), were searched for published literature from their inception to May 2023.RCTs that included CPMP were considered eligible regardless of fracture type.Language restrictions were not imposed.The keywords "pyrite", "pyritum", and "zirantong" were used for the search.The CPMP search was conducted in CNKI using CPMPs contained in the Chinese Pharmaceutical Dictionary and the Newly Edited National Chinese Traditional Patent Drugs.

Inclusion and Exclusion Criteria 2.2.1. Study Types
Prospective RCTs evaluating CPMP effectiveness for bone fractures were included.Other types of studies, such as non-RCTs, case reports, review articles, and animal experiments, were excluded.The exclusion criteria were studies (1) reporting diseases not related to fractures; (2) reporting unclear outcomes; (3) without outcome information; (4) not eligi-ble for outcome measurements; and (5) duplicates.Studies of parenteral administration, such as the external use of CPMP, were excluded.

Participant Types
Patients diagnosed with fractures by radiographic examination or who met the Chinese standard fracture diagnostic criteria [27] were included in the study regardless of fracture sites and types.There were no restrictions on patient age, sex, or nationality.

Intervention and Control Types
The concomitant administration of CPMP and application of conventional treatments, such as reduction, fixation, and Western medication, were analyzed as an intervention group; however, there were no specific criteria for CPMP administration type or duration.The control group was set as having administration of either conventional treatments or Western medication.The patients of both the intervention and control groups should have received the same conventional treatment.

Outcome Measurement Types
The measured primary outcome was the efficacy rate, including the total effective rate, callus growth rate, bone union, and edema disappearance time.
The assessed secondary outcomes were pain reduction-using the visual analog scale (VAS)-and pain disappearance time.The erythrocyte sedimentation rate (ESR), hematocrit (Hct), erythrocyte aggregation (EA), and plasma viscosity (PV) were evaluated using the blood test results.

Data Extraction
Identified articles were managed using Endnote software (version 20) (Clarivate, London, UK) for inclusion eligibility and screened based on the inclusion and exclusion criteria; duplicate articles were manually removed.For the selected studies, two researchers (anonymized for review) independently extracted the following data using a predefined MS Excel (Microsoft Office 2016, Microsoft Corp., Redmond, WA, USA) format: author, year of publication, study design, participants characteristics (age and sex), sample size, diagnostic criteria of fracture, classification of diseases, detailed information on the intervention and control treatments (method, duration, and dosage), main outcome measurements, results, adverse effects, and blinding method.Disagreements or uncertainties between researchers were resolved by discussion with a third reviewer (anonymized for review).

Data Analyses
After extracting the necessary data from the selected literature, a meta-analysis was conducted using Cochrane Review Manager 5.4.1 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).The corresponding authors of the studies with missing information were contacted whenever possible to acquire and verify the data.When appropriate, data across the studies were pooled to conduct a meta-analysis using fixed or random effects.GRADEpro software (https://www.gradepro.org/,accessed on 1 January 2023) from the Cochrane Systematic Reviews was used to create tables with a summary of findings.If the necessary data were available, a subgroup analysis was performed for the different types of therapies available and compared with CPMP.The total effective rate and callus growth rate are presented as odds ratios (OR) and 95% confidence intervals (CI), while the continuous variables are presented as standardized mean difference (SMD) and 95% CI.Statistical heterogeneity was assessed by I 2 and p-values based on 95% CIs, where I 2 < 25% was considered low heterogeneity; I 2 = 25-50% was considered moderate heterogeneity; I 2 > 50% was considered high heterogeneity; and p < 0.05 was considered statistically significant.The meta-analysis used random-effects or fixed-effects models if the heterogeneity was significant or insignificant, respectively.A subgroup analysis was performed using the X2 test, and sensitivity analysis was conducted to determine the robustness of the merged results by deleting low-quality studies.Publication bias was evaluated using funnel plots.

Quality Assessment
The RCTs quality was evaluated using the Cochrane Risk of Bias tool version 5.1.0with the following aspects: random sequence generation, allocation concealment, blinding of patients and personnel, incomplete outcome data, selective reporting, and other types of bias.The assessment results were classified using "L", "U", and "H" to indicate low, uncertain, and high risk of bias, respectively.Quality assessment was independently performed by two researchers.If there were disagreements in the evaluations between the two researchers, the literature was rechecked.If a disagreement persisted, an agreement was reached through discussion with a third party.If information could not be obtained from an article for assessment, the corresponding author was contacted.

Ethics and Dissemination
Ethical approval and patient consent were not required because this meta-analysis was based on published research results.

Literature Search
The procedure for the literature search and screening is presented in Figure 1.Only pyrite-related studies, such as TCM or traditional herbal medicines, were selected for review from the relevant literature.A total of 1454 articles were identified, including 22 from EMBASE, 45 from PubMed, 2 from Cochrane, 1274 from CNKI, 9 from OASIS, 13 from KISS, and 89 from NDSL.Among them, 30 duplicate studies were excluded.After screening the titles and abstracts, 1021 studies that were not related to fractures or CPMP were excluded.The full texts of the 403 remaining articles were assessed for eligibility.In total, 371 articles were excluded for the following reasons: non-RCTs (such as case reports or review articles), animal experiments, unclear outcomes, no outcome information, ineligibility for outcome measurements, and other Chinese treatments in the intervention or control groups.Among the 32 selected studies, three studies were excluded because they did not present the results of the total effective rate, VAS, pain reduction, blood test, and other related results.Finally, 29 studies were included in this systematic review.

Study Characteristics
The characteristics of the 29 included studies are presented in Tables 1 and 2. Among the data of the 3206 collected patients, there were 1612 and 1594 patients in the treatment and control groups, respectively.They were aged 7-85 years; the age varied according to the location and etiology of the fracture.Diagnostic criteria were based on Chinese fracture diagnosis criteria.Most studies were conducted after undergoing surgery or administrating primary treatment.Although the diagnostic criteria differ slightly according to location, most were based on imaging and morphology.Table 3 summarizes the evidence and main effects of CPMP therapy on fractures.

Study Characteristics
The characteristics of the 29 included studies are presented in Tables 1 and 2. Among the data of the 3206 collected patients, there were 1612 and 1594 patients in the treatment and control groups, respectively.They were aged 7-85 years; the age varied according to the location and etiology of the fracture.Diagnostic criteria were based on Chinese fracture diagnosis criteria.Most studies were conducted after undergoing surgery or administrating primary treatment.Although the diagnostic criteria differ slightly according to location, most were based on imaging and morphology.Table 3 summarizes the evidence and main effects of CPMP therapy on fractures.

Quality Assessment
The methodological quality of the 29 included studies is summarized in Figure 3 and Table 5.The risk of bias in studies was assessed using the Risk of Bias 2.0 tool [57].The overall risk of bias, in one or more domains, was evaluated to be of "some concern" in 25 studies and "high" in four studies.In all other studies, the overall risk of bias was evaluated as "high".Regarding reporting detailed information about the randomization process, 13 studies were assessed as "low" risk, 12 studies as "unclear", and the remaining 4 studies as "high" risk.Allocation concealment assessed 16 studies as "high" risk and 13 studies as "unclear" risk.Blinding and selective response assessments of all the studies were assessed as "unclear" risks owing to the uncertainty of the information.In the incomplete outcome data and other biases, most studies were assessed as "low" risk, except for one study, which had incomplete outcome data.

Quality Assessment
The methodological quality of the 29 included studies is summarized in Figure 3 and Table 5.The risk of bias in studies was assessed using the Risk of Bias 2.0 tool [57].The overall risk of bias, in one or more domains, was evaluated to be of "some concern" in 25 studies and "high" in four studies.In all other studies, the overall risk of bias was evaluated as "high".Regarding reporting detailed information about the randomization process, 13 studies were assessed as "low" risk, 12 studies as "unclear", and the remaining 4 studies as "high" risk.Allocation concealment assessed 16 studies as "high" risk and 13 studies as "unclear" risk.Blinding and selective response assessments of all the studies     [29,30], Huoxuezhitong [33][34][35][36], Jieguwan [37,38], and Shangkejiegupian [41,[44][45][46][47]49,50,52,53] were used for analysis.Some studies used Western medication in both the intervention and control groups after surgery, such as vitamin D, Calcium [29], sodium chloride injection with cefazolin sodium pentahydrate [35], cefoxitin sodium with saline [36], eparin sodium injection [47], sodium aescinate [49], and diclofenac sodium injection [53].As a result, 682 of the 779 patients in the CPMP groups and 523 of the 760 patients in the control groups were effectively treated.Owing to the low heterogeneity among the trials (I 2 = 23%), a fixed-effects model was chosen for the meta-analysis.The CPMPs were superior to the control groups in terms of increased efficacy (OR, 0.30; 95% CI, 0.23-0.39;p < 0.001) (Figure 4A).

Callus Growth Rate
Seven studies [29,30,32,39,40,55,56] involving 1362 patients reported callus growth rates.The intervention groups used Guyuling [29,30], Guzhecuoshang [32], Sanhuajiegusan [39,40], or Shangkejiegupian52,53 to treat CPMP after surgery.Among the seven articles, two used vitamin D, calcium, calcitriol [29], oyster shell calcium and vitamin C [40] in both groups, and one study used benorilate [55] in the control group only.The remaining studies did not indicate the use of the drugs in the control group.A total of 655 out of the 694 patients in the CPMP groups and 535 out of the 668 patients in the control groups were effectively treated.Due to the absence of heterogeneity among the trials (I 2 = 0%), a fixed-effects model was chosen for the meta-analysis.CPMP treatments were more effective in increasing the callus growth rate than the control treatments (OR, 0.18; 95% CI, 0.12-0.27;p < 0.001) (Figure 4B).

Callus Growth Rate
Seven studies [29,30,32,39,40,55,56] involving 1362 patients reported callus growth rates.The intervention groups used Guyuling [29,30], Guzhecuoshang [32], Sanhuajiegusan [39,40], or Shangkejiegupian52,53 to treat CPMP after surgery.Among the seven articles, two used vitamin D, calcium, calcitriol [29], oyster shell calcium and vitamin C [40] in both groups, and one study used benorilate [55] in the control group only.The remaining studies did not indicate the use of the drugs in the control group.A total of 655 out of the 694 patients in the CPMP groups and 535 out of the 668 patients in the control groups were effectively treated.Due to the absence of heterogeneity among the trials (I 2 = 0%), a fixed-effects model was chosen for the meta-analysis.CPMP treatments were more effective in increasing the callus growth rate than the control treatments (OR, 0.18; 95% CI, 0.12-0.27;p < 0.001) (Figure 4B).

Bone Union Evaluation
Five studies [29,30,38,45,51] involving 392 patients reported bone union evaluation; among them, 197 and 195 were included in the CPMP and control groups, respectively.The CPMP groups used Guyuling [29,30], Jieguwan [38], and Shangkejiegupian [45,51] postoperatively.Except for one article that used vitamin D, calcium, and calcitriol [26] in both groups, the other articles did not indicate the use of a drug in the control groups.Owing to the high heterogeneity among the trials (I 2 = 88%), a random-effects model was chosen for the meta-analysis.The CPMP treatments were more effective for bone union than in the control group treatments (SMD, −1.28, 95% CI, [−1.94, −0.63]; p < 0.001) (Figure 4C).
3.6.Outcomes (Secondary Outcomes: Pain Reduction) 3.6.1.VAS Seven studies involving 630 patients reported the VAS score, which were divided into 315 patients from the CPMP groups and 315 patients from the control groups.The CPMP groups used Guyuling [31], Huoxuezhitong [33,34], and Shangkejiegupian [41,47,53,54] postoperatively.Among them, sodium chloride injection with cefazolin sodium pentahydrate [35], heparin sodium injection [47], and diclofenac sodium injection [53] were used in both groups, whereas the other studies did not indicate the use of a drug in the control groups.Owing to the high heterogeneity among the trials (I 2 = 97%), a random-effects model was chosen for the meta-analysis.The difference of VAS score before and after treatment of the CPMP treatment groups was significantly higher than that of the control groups (SMD, −1.60; 95% CI, [−2.71, −0.48]; p = 0.005) (Figure 5A).

Hct
Four studies [28,43,44,48] involving 262 patients reported Hct.There were 131 patients from the CPMP groups and 131 patients from the control groups.The CPMP groups used Diedashenggukeli [28] and Shangkejiegupian [43,44,48] postoperatively, while the use of a drug was not indicated in the control groups.The meta-analysis used the SMD and random-effects model owing to the high heterogeneity among the trials (I 2 = 51%).The Hct of the CPMP treatment groups was significantly lower than that of the control groups (SMD, −0.72; 95% CI, [−1.08, −0.36]; p < 0.001; Figure 6B).

EA
Four studies [28,43,44,48] involving 262 patients reported EA.The CPMP and the control groups each comprised 131 patients.The CPMP groups used Diedashenggukeli [28] and Shangkejiegupian [43,44,48] postoperatively, while the use of a drug was not indicated in the control groups.The meta-analysis used the SMD and random-effects model, owing to the high heterogeneity among the trials (I 2 = 98%).The EA in the CPMP treatment groups was significantly lower than that in the control groups (SMD, −2.53; 95% CI, [−4.75, −0.31]; p = 0.03) Figure 6C).

PV
PV was reported in five studies [28,43,44,48,49] involving 322 patients.There were 161 patients from the CPMP groups and 161 patients from the control groups.The CPMP used Diedashenggukeli [28] and Shangkejiegupian [43,44,48,49] postoperatively.Sodium aescinate [49] was used in both groups, whereas the others did not indicate the use of a drug in the control groups.Owing to the high heterogeneity among the trials (I 2 = 92%), a random-effects model was chosen for the meta-analysis.The PV of the CPMP treatment groups was significantly lower than that of the control groups (SMD, −0.93; 95% CI, [−1.77, −0.09]; p = 0.03; Figure 6D).

Safety Assessment
Nine RCTs mentioned adverse effects or complications; among them, four RCTs reported the complications or adverse effects.In Zhou's study [36], rash occurred in the control group after the treatment administration, and there were no adverse effects in the CPMP group.Zhang and Zhong [38] reported complications that occurred after the administration of fracture treatment.In the CPMP groups, five complications were reported, including one case of fracture displacement, one case of delayed union, one case of dysfunction, and two cases of limb deformity.In the control groups, 16 complications were reported, including fracture displacement in three patients, delayed union in five patients, infection in two patients, dysfunction in three patients, and limb deformity in three patients.There was a statistically significant difference between the CPMP and control groups.He et al. [45] reported one case of deep vein thrombosis in the CPMP group; moreover, they reported one case of infection, three cases of deep vein thrombosis, and two cases of hematoma in the control group, which showed a statistically significant difference.Qiu et al. [51] reported 23 cases of fever and 20 cases of pain at the fracture site after the administration of fracture treatment in the CPMP group, and 23 cases of fever and 19 cases of pain in the control group.In summary, the total rate of complications or adverse effects was 62.5% for the CPMP groups and 61.54% for the control groups, with no statistical significance between the two groups.In addition, five patients experienced complications (two cases of delayed union and three cases of loosening of the internal fixture) in the CPMP groups, and 10 patients experienced complications (five cases of delayed union and five cases of loosening of the internal fixture) in the control groups.The incidences of complications in the CPMP and control groups were 12.5% and 25.64%, respectively, showing a statistically significant difference.

Bias Analysis
Publication bias was assessed using a funnel plot, which was evaluated for the total effective rate reported in 17 studies.A significant symmetry was observed for the distribution in the funnel plots (Figure 7).cations (two cases of delayed union and three cases of loosening of the internal fixture) in the CPMP groups, and 10 patients experienced complications (five cases of delayed union and five cases of loosening of the internal fixture) in the control groups.The incidences of complications in the CPMP and control groups were 12.5% and 25.64%, respectively, showing a statistically significant difference.

Bias Analysis
Publication bias was assessed using a funnel plot, which was evaluated for the total effective rate reported in 17 studies.A significant symmetry was observed for the distribution in the funnel plots (Figure 7).

Summary of Evidence According to Outcome Measures
For all outcome measures in the CPMP compared with the control trials, the overall quality of the evidence ranged from very low to moderate.Table 6 presents the GRADE assessment results.

Discussion
Fracture healing is a complex process involving various factors at the cellular and molecular levels, and various mechanisms involving the vasculature, lymphatic vessels, immune cells, polyadenylation, etc., have been reported.The vasculature and lymphatics have been reported to induce bone formation and hematopoietic regeneration [58,59], immune cells have been reported to play a pivotal role in fracture healing in bone, the unique tissue that constitutes the osteoimmune system [60,61], and the field of osteoimmunology continues to uncover new dimensions of the mutual interactions between bone and the immune system [60,62].In addition, the role of alternative polyadenylation as a post-transcriptional regulatory mechanism involved in transcriptome formation in fracture healing and regulation of gene expression during bone regeneration has recently been reported.During the fracture healing process, it can lead to various complications, such as delayed healing or non-union healing pattern [63].These complications are difficult to treat and cause a financial burden due to loss of productivity [64].Accordingly, any strategy that helps reduce the healing time aids in the rapid resumption of the work duties and daily activities by the patients, improvement of their medical outcomes, and reduction of their financial burden.Traditional medicines have been widely used to treat bone diseases for several centuries.According to TKM and TCM theories, the pathological symptoms of fractures are accompanied by redness, pain, and swelling at the fracture site, which may cause circulatory congestion or delay treatment [65].Studies examining TKM and TCM suggest that herbal medicines can improve fracture healing by controlling inflammation, promoting blood circulation, and stimulating bone formation [66].

Main Findings
This review aimed to establish evidence for the efficacy and safety of CPMP treatment of fractures.Twenty-nine RCTs, with a total of 3206 patients, were included.This study indicated CPMPs had higher therapeutic efficacy by significantly improving the callus growth rate, bone union, and edema disappearance time compared with the control groups receiving no treatment or Western medicine.Moreover, CPMP reduced the pain intensity and duration and had fewer complications without posing serious risks.
In fracture healing, the bone vasculature, a major component of the bone marrow microenvironment, plays a fundamental role in coordinating osteogenesis and hematopoiesis through the production of various angiocrine factors.The vasculature provides signals for the maintenance and proliferation of bone hematopoietic stem and progenitor cells and regulates the differentiation of perivascular mesenchymal stem cells to generate bone cells [58,59].Our review revealed that all parameters of the blood tests, namely ESR, PV, Hct, and EA, related to changes in the blood circulation and hematoma during fracture healing, were significantly improved in the CPMP groups compared with the control groups.These results suggest that CPMP treatment has an effect on the vascular system, which plays an important role in the fracture healing process.

CPMP Therapeutic Efficacy for Hematomas, a Critical Parameter in Fractures
In general, when a bone fracture occurs, the bone itself and the blood from the damage-induced bleeding in the connective tissue around the fracture coagulate, forming a hematoma.The hematoma in these fractured areas plays a role in biomechanically fixing the fracture area and biologically creating the outer structure of the tissue necessary for cell infiltration and vascular ingrowth.Therefore, many studies have reported that hematomas play an important role in bone fracture healing [67,68], and studies on promoting the fracture healing process have reported that it is important to rapidly improve the blood flow in the fractured area during the fracture healing process [69].
Pyritum is a mineral that is used to treat fractures in KM and TCM.Mineral medicines have been used for more than 4000 years.There are 82 and 34 types of mineral medicines out of 5676 and 514 types of medicines in the Dictionary of Traditional Chinese Medicine and The Korean Herbal Pharmacopeia, respectively.In China, mineral medicines are recognized as equally important to animal-and vegetable-derived medicines, and research has been conducted on these medicines using modern scientific methods since the late 1970s.However, in the Republic of Korea, there is a lack of systematic mineral herbal medicine research, and some mineral medicines contain heavy metals, such as mercury, arsenic, lead, and copper, which limits their use and results in the scarcity of literature in that respect [70].
In China, a CPM formulation is widely used to clinically treat various diseases [71].CPMs are manufactured according to the monographs of the Pharmacopeia of the People's Republic of China using specific formulas stipulated by the Chinese law [25] and are considered clinically easier to formulate and safer to use than herbal decoctions owing to the laws and regulations [72].The use of CPMP has been verified throughout the whole process from the beginning to the second half of the fracture, resulting in a significant increase in the osteoid thickness and mineral apposition rate and rapid stimulation of callus formation, osteoid formation, and maturity compared to that in the saline control group.Moreover, CPMP can be used as a treatment for delayed fracture healing or failure to achieve a normal fracture union [69].In this study, seven types of CPMP (Diedashenggukeli, Guyulingjiaonang, Guzhecuoshangjiaonang, Huoxuezhitong, Jieguwan, Sanhuajiegusan, and Shangkejiegupian) were selected from the 33 CPMP types included in the Pharmaceutical Dictionary and the Newly Edited National Chinese Traditional Patents.Despite long-term use and therapeutic efficacy, there is a limited number of clinical trials investigating traditional mineral medicines, including pyritum, as remedies for fracture treatment.Moreover, there are no relevant systematic reviews or meta-analyses investigating the effect of CPMPs.This study serves as a reference for clinical use and the diverse research application of traditional mineral medicines, including pyritum.
In this study, CPMP was mostly used after reduction or fixation, such as open reduction and internal fixation or manual reduction and splinting.Although surgical treatment can effectively restore the anatomical position of the fracture and provide strong fixation, it has no obvious effect on the recovery of fracture healing.A previous study reported that postoperative side effects or complications may occur from delayed healing due to hematoma after the fracture [73].To prevent complications during fracture healing, traditional medicine suggests that activating blood circulation and removing stagnation can promote the absorption and dissipation of blood, thereby removing harmful elements and creating favorable conditions for fracture healing [74].The seven CPMPs included in this study are considered ideal selections of compounds because they have shown common efficacy in promoting blood circulation, dispelling blood stasis, reducing swelling, and relieving pain.Most of the individual components included in the seven CPMPs were blood-activating and stasis-dispelling medicinals.Excluding pyrite, the most used Tubiechong in CPMPs is an insect medicine that has the action of releasing blood stasis, facilitating blood circulation, eliminating lumps and masses, weaving tendons, and connecting bones in the Chinese Pharmacopoeia, and is included in more than 200 types of Chinese patent medicines [75].In a previous study reporting TCM utilization patterns in patients with fractures [65], the single most prescribed herbs were Gusuibu and Xuduan, for strengthening tendons and bones, Yanhusuosuo, for moving qi and reducing pain, and for blood-quickening, stasis-transforming herbs including Danshen.In this study, the use of the mentioned herbs was confirmed.In TCM, theoretical grounds for the therapeutic effect of CPMP on fractures can be found, but additional research is needed to find the optimal combination of medicines including pyrite.

CPMP Safety
Regarding safety, four RCTs reported complications and side effects following the CPMP use.Postoperatively, the control groups received no treatment, and the treatment group received CPMP.One of the two studies reporting side effects revealed that there were no side effects in the CPMP group; however, rash occurred in the cefoxitin sodium + saline group postoperatively, which was considered to be related to cefoxitin sodium.In another report, fever and pain occurred in both the CPMP and control groups; however, there was no significant difference between the two groups.Regarding complications, three studies (one related to Jieguwan and two related to Shangkejiegupian) reported postoperative fracture dislocation, delayed union, functional disorder, infection, and deep vein thrombosis.Incidences of these complications were significantly lower in the CPMP group than in the control groups.
Fracture healing is a complex process involving various factors at the cellular and molecular levels and can lead to various complications, such as delayed healing or nonunion healing pattern [63].These complications are difficult to treat and result in a financial burden owing to the loss of productivity [66].Accordingly, any strategy that helps reduce the healing time aids in the rapid resumption of work duties and daily activities by the patients, improvement of their medical outcomes, and reduction of their financial burden.As noted in our study, there were no serious side effects caused by CPMP, and the incidence of complications in the CPMP groups was lower than that in the control groups.Therefore, CPMP may be a relatively safe treatment strategy for fracture patients and can be used to reduce postoperative complications.Because adverse effects were not reported in most studies, the active observation of adverse effects and safety-related studies are needed for the safe clinical application of CPMP in the future.

Limitations and Suggestions for Further Studies
This study had several limitations.First, most of the included studies demonstrated high heterogeneity, publication bias, and regional bias.This could be attributed to the randomized-trial design of the included studies; however, there were no specific randomized trials for random sequence generation, allocation concealment, or outcome assessment blinding, and only 29 RCTs that were published in the same country were included.Second, seven types of CPMP were included for fracture treatment.High heterogeneity was observed owing to the different types of CPMPs, controls, and unequal treatment durations.Therefore, caution should be exercised when interpreting these results.Third, although CPMP had a statistically significant effect on treatment efficacy, pain reduction, and hematological change improvement in patients with fractures, most studies had a high risk of bias.In the future, high-quality clinical trials, with high validity and reliability and using a more rigorous methodology, are needed to evaluate the potential benefits of CPMP therapy for fractures.
Existing studies suggest that pyritum is useful for fracture treatment; however, no clinical trial has investigated this effect.However, clinical evidence could not be validated because pyritum was not used alone.Various clinical studies are required to verify the efficacy and safety of pyritum alone.Although limitations still persist in terms of the legal and clinical aspects of pyritum administration worldwide, this study could serve as a basis for the development of more treatment alternatives to patients with fractures, and for the design of future clinical studies.

Figure 1 .
Figure 1.PRISMA flow chart diagram.CNKI, China National Knowledge Infrastructure; OASIS, Oriental Medicine Advanced Searching Integrated System; KISS, Korean Studies Information Service; NDSL, National Digital Science Library; RCTs, randomized controlled trials; CPMP, Chinese patent medicines containing pyritum, TCM, traditional Chinese medicine.

Figure 1 .
Figure 1.PRISMA flow chart diagram.CNKI, China National Knowledge Infrastructure; OASIS, Oriental Medicine Advanced Searching Integrated System; KISS, Korean Studies Information Service; NDSL, National Digital Science Library; RCTs, randomized controlled trials; CPMP, Chinese patent medicines containing pyritum, TCM, traditional Chinese medicine.

Figure 2 .
Figure 2. Frequently used ingredients in Chinese patent medicine containing pyrite (CPMP) for fractures.

Figure 3 .
Figure 3. Risk of Bias 2.0 summary: authors' judgements for each risk of bias domain across all included studies.

Table 2 .
Characteristics of RCTs for the treatment of fractures.

Table 3 .
Summary of the evidence and effects of CPMP interventions for fractures.

Table 4 .
Overview of CPMP ingredients for fractures.

Table 5 .
Methodological quality of included studies according to the tool Risk of Bias 2.0.

Table 5 .
Methodological quality of included studies according to the tool Risk of Bias 2.0.
D1-D5: 5 domain criteria; D1, bias arising from the randomization process; D2, bias due to deviations from intended interventions; D3, bias due to missing outcome data; D4, bias in the measurement of the outcome; D5, bias in the selection of the reported results.;H: high risk of bias; L: low risk of bias; Sc: some concerns.

Table 6 .
Summary of study findings in this meta-analysis.